Laboratório Igenomix, Laboratório de Genética E Medicina Reprodutiva, Sao Paulo, Sao Paulo, Brazil.
IGENOMIX Lab S.L.U., Parque tecnológico, Ronda Narciso Monturiol, 11B, Edificios Europark, 46980, Paterna, Valencia, Spain.
Eur J Med Res. 2021 Jun 29;26(1):64. doi: 10.1186/s40001-021-00535-5.
Since 2011, screening maternal blood for cell-free foetal DNA (cffDNA) fragments has offered a robust clinical tool to classify pregnancy as low or high-risk for Down, Edwards, and Patau syndromes. With recent advances in molecular biology and improvements in data analysis algorithms, the screening's scope of analysis continues to expand. Indeed, screening now encompassess additional conditions, including aneuploidies for sex chromosomes, microdeletions and microduplications, rare autosomal trisomies, and, more recently, segmental deletions and duplications called copy number variations (CNVs). Yet, the ability to detect CNVs creates a new challenge for cffDNA analysis in couples in which one member carries a structural rearrangement such as a translocation or inversion.
We report a segmental duplication of the long arm of chromosome 3 and a segmental deletion of the short arm of chromosome 5 detected by cffDNA analysis in a 25-year-old pregnant woman. The blood sample was sequenced on a NextSeq 550 (Illumina) using the VeriSeq NIPT Solution v1 assay. G-band karyotyping in amniotic fluid only detected an abnormality in chromosome 5. Next-generation sequencing in amniocytes confirmed both abnormalities and identified breakpoints in 3q26.32q29 and 5p13.3p15. The foetus died at 21 weeks of gestation due to multiple abnormalities, and later G-band karyotyping in the parents revealed that the father was a carrier of a balanced reciprocal translocation [46,XY,t(3;5)(q26.2;p13)]. Maternal karyotype appeared normal.
This case provides evidence that extended cffDNA can detect, in addition to aneuploidies for whole chromosomes, large segmental aneuploidies. In some cases, this may indicate the presence of chromosomal rearrangements in a parent. Such abnormalities are outside the scope of standard cffDNA analysis targeting chromosomes 13, 18, 21, X, and Y, potentially leading to undiagnosed congenital conditions.
自 2011 年以来，筛查母体血液中的游离胎儿 DNA（cffDNA）片段为唐氏综合征、爱德华氏综合征和帕陶氏综合征的低危或高危妊娠提供了一种强有力的临床工具。随着分子生物学的最新进展和数据分析算法的改进，筛查的分析范围不断扩大。事实上，筛查现在涵盖了其他情况，包括性染色体非整倍体、微缺失和微重复、罕见的常染色体三体以及最近的片段缺失和重复，称为拷贝数变异（CNVs）。然而，检测 CNVs 的能力为携带结构重排（如易位或倒位）的夫妇中的 cffDNA 分析带来了新的挑战。
我们报告了一例 25 岁孕妇通过 cffDNA 分析检测到的 3 号染色体长臂片段重复和 5 号染色体短臂片段缺失。该血液样本在 NextSeq 550（Illumina）上使用 VeriSeq NIPT Solution v1 试剂盒进行测序。羊水的 G 带核型分析仅发现 5 号染色体异常。羊水细胞的新一代测序证实了这两种异常，并在 3q26.32q29 和 5p13.3p15 处鉴定了断点。由于多种异常，胎儿在 21 周时死亡，随后对父母进行的 G 带核型分析显示，父亲是平衡易位[46,XY,t(3;5)(q26.2;p13)]的携带者。母亲的核型正常。
本病例提供了证据，表明扩展的 cffDNA 除了可以检测整条染色体的非整倍体外，还可以检测大片段的非整倍体。在某些情况下，这可能表明父母一方存在染色体重排。这些异常超出了针对 13、18、21、X 和 Y 染色体的标准 cffDNA 分析范围，可能导致未诊断的先天性疾病。
